Carbon Nanotube Biodegradation by Neutrophil Myeloperoxidase PI: Valerian E. Kagan, PhD, DSc Widespread applications of engineered nanomaterials, particularly carbon nanotubes (CNT), in different spheres of industry, consumer products, and medicine raise concerns about their possible adverse effects on human health in occupational settings and in the environment. The unique physico-chemical characteristics combined with the vast surface area make the biological effects of CNT largely unpredictable. Our in vivo studies have demonstrated robust and unusual pulmonary inflammatory/oxidative stress responses to single walled CNT (SWCNT) upon exposure of mice via aspiration or inhalation. To date, no demonstration of biodegradation of carbon nanotubes in a physiologically relevant setting has been provided. Our Preliminary results demonstrate that strong oxidants such as hypochlorous acid and oxoferryl species generated as reactive products of the myeloperoxidase reaction may be effective in biodegrading SWCNT. Therefore, we hypothesized that myeloperoxidase in neutrophils has the ability to catalyze the biodegradation of SWCNT and inactivate them inducers of inflammatory responses. To determine the extent to which enzymatic catalysis by human neutrophil myeloperoxidase (hMPO) represents a novel route of biodegradation of SWCNT, we designed experiments formulated in three Specific Aims of the proposal as follows: Specific Aim 1 will determine molecular mechanisms, products and reaction pathways through which hMPO catalyzes biodegradation of SWCNT. Specific Aim 2 will define the conditions maximizing biodegradation of SWCNT in human neutrophils and determine possible contribution and role of neutrophil interactions with macrophages in the biodegradation process through the formation of redox phagocytic synapse. Specific Aim 3 will elucidate hMPO-catalyzed biodegradation of single-walled carbon nanotubes by neutrophils in vivo and quantitatively assess the contribution of the biodegradation process in mitigation of the SWCNT induced inflammatory responses in mouse lung. Discovery of a novel enzymatic pathway for "green" biochemical biodegradation of carbon nanotubes may revolutionize the ways to regulate their distribution in the body and contribute to a roadmap to new effective approaches to decrease their toxicity. PUBLIC HEALTH RELEVANCE: Carbon Nanotube Biodegradation by Neutrophil Myeloperoxidase PI: Valerian E. Kagan, PhD, DSc Widespread applications of engineered nanomaterials, particularly carbon nanotubes (CNT), in different spheres of industry, consumer products, and medicine raise concerns about their possible adverse effects on human health in occupational settings and in the environment. Based on known robust and unusual pulmonary pro-inflammatory effects of CNT, identification of their biodegradation pathways becomes a necessity. We demonstrate that an enzyme of neutrophils - myeloperoxidase - has the ability to catalyze biodegradation of SWCNT and inactivate them as inducers of pulmonary inflammation thus indicating new ways to regulate their distribution in the body and reduce the toxicity.